Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy

利用嘧啶核苷酸合成依赖性进行 IDH 突变胶质瘤治疗

• 批准号: 10180738
• 负责人: Kalil G Abdullah
• 金额: $ 37.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-07 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180738
• 关键词: Achievement; Address; Adult Glioma; Anabolism; Apoptosis; Biological; Biological Markers; Brain; Brain Neoplasms; Branched-Chain Amino Acids; Catabolism; Cell Death; Cell Survival; Cells; Central Nervous System Neoplasms; Chemicals; Chromatin Structure; Clinic; Clinical; Clinical Trials; Coupled; DHODH gene; DNA biosynthesis; Defect; Dependence; Dihydroorotate dehydrogenase; Disease; Disease model; Drug Targeting; Endoplasmic Reticulum; Enzyme Inhibitor Drugs; Enzymes; FDA approved; Foundations; Functional disorder; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Heterogeneity; Glioblastoma; Glioma; Glutaminase; Glutamine; Goals; Homeostasis; Human; Hypersensitivity; Impairment; Individual; Isocitrate Dehydrogenase; Lipids; Malignant - descriptor; Malignant Neoplasms; Medical; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mutate; Mutation; Newly Diagnosed; Oncoproteins; Organoids; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phospholipids; Pre-Clinical Model; Predisposition; Primary Brain Neoplasms; Production; Protein Glycosylation; Proteins; Pyrimidine; Pyrimidine Nucleotides; Pyrimidine Synthesis Inhibition; RNA chemical synthesis; Radiation therapy; Research; Resistance; Role; Stress; Surveys; Survival Rate; System; Testing; Therapeutic; Tissues; Translating; Tumor Cell Line; United States; Work; cancer therapy; clinical translation; combat; design; endoplasmic reticulum stress; experimental study; gain of function; glioma cell line; in vivo; inhibitor/antagonist; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; patient derived xenograft model; pre-clinical; preclinical trial; predicting response; predictive marker; research clinical testing; response; standard care; success; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for new ways to combat this disease, the standard treatment for gliomas has not changed since 2005 and no new glioma medical therapies have been approved in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in a gene called IDH1. IDH1 mutations are present in 70-90% of lower grade gliomas and secondary glioblastomas, a highly aggressive subtype of glioma. We surveyed hundreds of drugs and discovered that a class of drugs that inhibit a particular metabolic pathway preferentially killed brain tumor cells with IDH1 mutations. Our proposal builds on this discovery by addressing three Specific Aims. Specific Aim #1 is to understand the molecular mechanisms through which IDH1 mutations increase sensitivity to inhibitors of this metabolic pathway. We will use cultured brain tumor cell lines that harbor or lack IDH1 mutations to test our hypothesis that the combined effects of IDH1 mutations and these inhibitors severely impair protein processing and lipid production in tumor cells, creating stress that ultimately triggers cell death. Specific Aim #2 is to use organoid models derived from human glioma tissue to assess whether the presence of an IDH1 mutation successfully predicts response to inhibitors of the metabolic pathway we propose targeting. Organoids represent powerful preclinical disease models because they allow us to test new therapeutic strategies in a cellular system that accurately reflects the makeup of human brain tumors. Specific Aim #3 is to use a mouse model of glioma to assess whether inhibiting the metabolic pathway we've identified to be important for IDH1 mutant brain tumor cells leads to desirable therapeutic responses, including a block in tumor growth and extension of host survival. These studies will clarify whether targeting this pathway is likely to provide benefit for human patients with IDH1 mutated brain tumors. Taken together, our work will outline and test a new treatment strategy for brain tumor patients that could be rapidly translated to the clinic if our studies are successful. Furthermore, our efforts may demonstrate that IDH1 mutations can be used to faithfully identify individuals whose tumors are poised to respond to the treatment strategy we are developing, thereby providing a way to design potential future clinical trials that have the greatest chance to provide benefit for glioma patients.

项目摘要 神经胶质瘤占26，000例新诊断的脑和中枢神经系统恶性病例的80% 在美国每年发生的恶性肿瘤，是最致命和最难治疗的人类癌症之一。 尽管迫切需要新的方法来对抗这种疾病，但神经胶质瘤的标准治疗方法还没有 自2005年以来发生了变化，过去十年没有新的胶质瘤医学疗法获得批准。响应 为了应对这一挑战，我们设计了一种新的方法来治疗在IDH1基因中有突变的胶质瘤。IDH1 突变存在于70 - 90%的低级别胶质瘤和继发性胶质母细胞瘤中， 胶质瘤亚型。我们调查了数百种药物，发现一类抑制特定药物的药物 代谢途径优先杀死具有IDH1突变的脑肿瘤细胞。我们的建议建立在这一基础上 通过解决三个具体目标的发现。具体目标#1是了解分子机制 IDH1突变通过其增加对该代谢途径的抑制剂的敏感性。我们将使用培养 携带或缺乏IDH1突变的脑肿瘤细胞系，以检验我们的假设，即IDH1 突变和这些抑制剂严重损害肿瘤细胞中的蛋白质加工和脂质产生， 最终引发细胞死亡的压力具体目标#2是使用衍生自人神经胶质瘤的类器官模型 组织以评估IDH1突变的存在是否成功地预测了对免疫抑制剂的应答。 代谢途径我们提出的目标。类器官代表了强大的临床前疾病模型，因为它们 使我们能够在细胞系统中测试新的治疗策略，准确地反映人类的组成， 脑瘤具体目标#3是使用神经胶质瘤的小鼠模型来评估是否抑制代谢性神经胶质瘤。 我们已经确定的IDH1突变脑肿瘤细胞的重要途径导致了理想的治疗 反应，包括阻断肿瘤生长和延长宿主存活。这些研究将阐明， 靶向该途径可能为患有IDH1突变脑肿瘤的人类患者提供益处。采取 我们的工作将共同概述和测试一种新的脑肿瘤患者治疗策略， 如果我们的研究成功的话就能应用到临床上此外，我们的努力可能表明IDH1 突变可用于忠实地识别肿瘤对治疗有反应的个体， 我们正在制定的战略，从而提供一种方法来设计潜在的未来临床试验， 为神经胶质瘤患者提供获益的机会。